Transplantation is the act of transferring cells, tissues, or organs from one site to another. The malfunction of an organ system may be corrected with transplantation of an organ (e.g., kidney, liver, heart, lung, or pancreas) from a donor. However, the immune system remains a most formidable barrier to transplantation as a routine medical treatment. The immune system has developed elaborate and effective mechanisms to combat foreign agents. These mechanisms are also involved in the rejection of transplanted organs, which are recognized as foreign by the recipient's immune system.
Understanding these mechanisms is important, as it aids in understanding the clinical features of rejection and, hence, in making an early diagnosis and delivering appropriate treatment. Knowledge of these mechanisms is also critical in developing strategies to minimize rejection and in developing new drugs and treatments that blunt the effects of the immune system on transplanted organs, thereby ensuring longer survival of these organs.
The degree of immune response to a graft depends partly on the degree of genetic disparity between the grafted organ and the host. Xenografts, which are grafts between members of different species, have the most disparity and elicit the maximal immune response, undergoing rapid rejection. Autografts, which are grafts from one part of the body to another (e.g., skin grafts), are not foreign tissue and, therefore, do not elicit rejection. Isografts, which are grafts between genetically identical individuals (e.g., monozygotic twins), also undergo no rejection. Allografts are grafts between members of the same species that differ genetically. This is the most common form of transplantation. The degree to which allografts undergo rejection depends partly on the degree of similarity or histocompatibility between the donor and the recipient.
The degree and type of response also vary with the type of the transplant. Some sites, such as the eye and the brain, are immunologically privileged. Skin grafts are not initially vascularized and so may not manifest rejection until the blood supply develops. The heart, kidneys, and liver are highly vascular organs and can lead to a vigorous cell mediated response in the host.
One of the more common transplantations relates to blood stem cells, particularly allogeneic stem cell transplants, for example in the treatment of cancer, and which have promise for the treatment of blood diseases such as sickle cell anemia, thalassemias, and the like. In an allogeneic transplant, stem cells are collected from a matching donor and transplanted into the patient to suppress the disease and restore the patient's immune system. An allogeneic stem cell transplant is different from an autologous stem cell transplant, which uses stem cells from the patient's own body. Donor cells may be circulating stem/progenitor cells; mobilized peripheral blood, cord blood, etc. Before an allogeneic stem cell transplant, patients are typically treated with intensive high-dose chemotherapy, or a combination of high-dose chemotherapy and radiation therapy. Because immune cells are transferred in the process, however there can be a risk of graft-versus-host-disease (GVHD), a condition where the donated cells attack recipient tissues.
Included in the field of solid organ transplants is the transplantation of pancreatic islet cells. While significant progress has been made, many obstacles remain that preclude its widespread application. An important limitation are the currently inadequate means for preventing islet rejection. Current immunosuppressive regimens are capable of preventing islet failure for months to years, but the agents used in these treatments are expensive and can increase the risk for specific malignancies and opportunistic infections. Further, calcineurin inhibitory immunosuppressive agents such as cyclosporine, FK-506, rapamycin, etc. are known to impair normal islet function and/or insulin action. Of particular concern is the harmful effect of certain widely employed immunosuppressive agents on renal function. For a patient with diabetes, renal function is a crucial factor in determining long-term outcome, and calcineurin inhibitors show significant nephrotoxicity. For diabetic patients, even those with long-standing and difficult-to-control disease, the prognosis for survival can be comparatively much better treating with insulin vs. transplantation. While most islet recipients achieve better glycemia control and suffer less serious hypoglycemia, islet transplantation currently continues to fall short of the definitive diabetes cure.
Improved methods of improving patient health following transplantation is of great interest, including providing efficient therapeutic strategies targeting GVHD, with lower side effects.